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Health- and vision-related quality of life in patients receiving infliximab therapy for Behçet uveitis
  1. Tsutomu Sakai,
  2. Hiroka Watanabe,
  3. Kana Kuroyanagi,
  4. Goichi Akiyama,
  5. Kiichiro Okano,
  6. Hideo Kohno,
  7. Hiroshi Tsuneoka
  1. Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
  1. Correspondence to Dr Tsutomu Sakai, Department of Ophthalmology, Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan; ski1124{at}live.jp

Abstract

Objective To evaluate the changes in health-related and vision-related quality of life (HR-QoL and VR-QoL) in patients with Behçet uveitis (BU) receiving infliximab therapy.

Methods Twenty patients with recurrent BU attacks were enrolled. All patients were treated with infliximab. We evaluated the mean number of uveitis attacks and the mean score of extraocular manifestations by Behçet disease current activity form (BDCAF) during the 6 months before and the 6 and 12 months after initiation of infliximab. The EuroQol-5D questionnaire (EQ-5D) and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) were self-administered in all patients before treatment and, 6 and 12 months after treatment. Patients’ pre- and post-treatment EQ-5D and NEI VFQ-25 scores were compared.

Results By the 6- and 12-month follow-up, the frequency of uveitis attacks and the BDCAF scores was significantly decreased compared with the 6 months before starting infliximab (p<0.0001). Fully completed questionnaires were received from all patients. Infliximab therapy was associated with a significant improvement of the EQ-5D (p<0.0001), NEI VFQ-25 composite score (p=0.0001), general health score (p=0.0001) and mental health score (p=0.0001). This result shows a significant decrease in inflammatory activity of the disease and consequently improvement in HR-QoL and VR-QoL scores with a rising response pattern in all dimensions.

Conclusions Relief of uveitis attacks and extraocular manifestations by infliximab therapy significantly improved the HR-QoL and VR-QoL in patients with BU.

  • Inflammation
  • Drugs

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Introduction

Behçet disease (BD) is a rare, chronic, systemic, inflammatory disorder characterised by recurrent ocular, oral, genital and skin lesions.1 Behçet uveitis (BU) often begins several years after disease onset and affects the posterior segment of the eye in an estimated 50% of patients, causing conditions such as retinal vasculitis, macular oedema and papillitis. These ocular lesions threaten the patient's sight and thus patients with active BU may have a reduced quality of life (QoL). Indeed, recent studies have shown deficits in health-related QoL (HR-QoL) for several physical functions and mental health items.2

Treatment with disease-modifying immunosuppressive drugs can reduce the number of uveitis attacks and improve the visual outcome in BU.3 ,4 However, conventional treatment does not produce an effective response in about 50% of patients. These patients still experience uveitis attacks and have a poor visual prognosis. Recent pharmacological treatment has focused on the use of biological agents. Infliximab, a chimeric monoclonal anti-tumour necrosis factor α antibody, comprising a human IgG1κ antibody with a mouse Fv of high affinity and neutralising activity, has been shown to reduce ocular attacks in BU significantly and to improve visual outcome.5 ,6 A recent study has also shown long-term remission of ocular and extraocular manifestations in BU using infliximab.7

The purpose of this study was to evaluate changes in HR-QoL and vision-related QoL (VR-QoL) in patients with BU receiving infliximab therapy. We used the EuroQol-5D questionnaire (EQ-5D) and the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) to compare QoL before treatment with that after 6 and 12 months of treatment. We also evaluated the frequency of uveitis attacks and changes in extraocular manifestations using the Behçet disease current activity form (BDCAF) score in these patients.

Methods

Twenty patients who had been diagnosed with BU at Jikei University Hospital between 1 April 2007 to 31 December 2010 and still had persistent disease activity after conventional treatment were recruited into this prospective study. Diagnostic criteria were those defined by the BD research committee of Japan.8 ,9 Eligibility criteria included at least 18 months of follow-up and no other systemic or ocular disease that might affect vision. All patients were Japanese. The study was approved by the ethics committee of Jikei University and conducted according to the Declaration of Helsinki. Informed consent was obtained from all patients.

All patients underwent a complete ophthalmological examination, including best-corrected visual acuity, slit lamp biomicroscopy, tonometry and indirect ophthalmoscopy. Visual acuity was evaluated using a Snellen chart on a scale of 0.1–1.5.

Ocular clinical data were collected for the number of acute episodes of uveitis (uveitis attacks) during the 6 months before (pretreatment period) and in the 6 and 12 months after (post-treatment period) initiation of infliximab. In our hospital, patients with posterior segment involvement of BU are prescribed colchicine on diagnosis. Flare-up of uveitis is managed by the use of corticosteroids (periocular or oral) or an immunosuppressive agent (ciclosporin). Patients whose disease is refractory to immunosuppressive agents are prescribed biological agents (infliximab). Infliximab was given intravenously at a dose of 5 mg/kg, followed by additional doses at 2 and 6 weeks after the first dose and every 8 weeks thereafter. From the fifth administration, the treating ophthalmologist had the option of shortening the infusion interval (typically by infusing infliximab with an interval of fewer than 49 days). Information was collected at 6 and 12 months after the initial treatment.

Extraocular manifestations were assessed using the BDCAF score.10 This form scores (from 0–4) the duration of clinical features (oral ulcers, genital ulcers, skin lesions, joint symptoms or intestinal symptoms) that were present during the 4 weeks before the day of assessment. Each episode of a manifestation was judged by a physician and dermatologist. The BDCAF score was collected at the time of infliximab initiation and 6 and 12 months later. This instrument offers an easy-to-complete and reliable method of assessing and documenting clinical activity in patients with BD for use in routine clinical practice.

EQ-5D

The EQ-5D, a widely used measure of generic HR-QoL, was used to examine overall aspects of HR-QoL. The EQ-5D was self-administered by the 20 patients before and after treatment. The Japanese version of the EQ-5D, which has been modified in accordance with Japanese culture and lifestyle, was used. This modified EQ-5D has been evaluated for its reliability and validity and has been proved to measure HR-QoL accurately in Japanese subjects.11 ,12 The EQ-5D has five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Three response categories are available for each dimension, describing 243 different health states. The Japanese tariff translates EQ-5D scores into utilities by a time trade-off technique. The potential EQ-5D value ranges from −0.59 to 1.0. Typically a difference of 0.06–0.07 is considered clinically meaningful.13–15

NEI VFQ-25

The NEI VFQ-25 was self-administered by the 20 patients before and after treatment. The Japanese version of the NEI VFQ-25, which has been modified in accordance with Japanese culture and lifestyle, was used. The modified NEI VFQ-25 has been assessed for its reliability and validity and has been proved to measure VR-QoL accurately in Japanese subjects.16 The NEI VFQ-25 comprises 12 vision-targeted scales: general health, general vision, ocular pain, near activities, distant activities, social functioning, mental health, role difficulties, dependency, driving, colour vision and peripheral vision. Each scale consists of a minimum of one and a maximum of four items. Subscales were scored on a scale of 0 (worst) to 100 points (best). Typically a difference of four to six points is considered clinically meaningful.15 ,17 Scores were calculated using the recommendations of the developers of the questionnaire and according to published guidelines for the NEI VFQ-25. The mean scores and SD were calculated for each subscale and the composite score was calculated by averaging the scores of 11 subscales; the general health subscale was excluded.

Statistical analysis

A Wilcoxon signed rank test or Mann–Whitney U test was used to compare results before and after treatment. Comparisons were considered to be significant for a p value <0.05. All analyses were carried out using Intercooled Stata V.7.0 (Stata Corporation, College Station, Texas, USA).

Results

The characteristics of the 20 patients treated with infliximab are presented in table 1. The study population included 12 men and eight women, with a mean (SD, range) age of 45 (14, 24–71) years. The interval between the onset of uveitis and infliximab therapy, treatment before starting infliximab, number of uveitis attacks and occurrence of extraocular manifestations in the 6 months before and 6 and 12 months after treatment are shown in table 1. Twelve of the 20 patients (60%) had no uveitis attacks during the entire 12-month period. Patients (30%) with continued recurrence of attacks required more frequent doses of infliximab. Patient 14 had recurrent attacks even when a 6-week infusion interval was used and therefore we used methotrexate as concomitant treatment with infliximab and managed to control the uveitis attacks. Patients 15 and 17 had recurrence of uveitis attacks and extraocular manifestations in treatment with the standard infusion interval, but neither patient had recurrence after introduction of a 7-week infusion interval.

Table 1

Clinical features of patients with Behçet uveitis receiving infliximab (IFX) before and after treatment

The mean numbers of uveitis attacks that occurred 6 months before and 6 and 12 months after initiation of infliximab were 3.7±2.2, 0.6±0.7 and 0.3±0.9, respectively (figure 1). These data show that infliximab significantly reduced the number of attacks (p<0.0001). The rates of occurrence of extraocular manifestations 6 months before and 6 and 12 months after initiation of infliximab were 100% (20/20), 15% (3/20) and 5% (1/20), respectively. Thus, infliximab also significantly reduced the occurrence of extraocular manifestations (p<0.0001). There was also a significant difference between mean BDCAF scores for extraocular manifestations before starting infliximab compared with those 6 and 12 months after the start of treatment (p<0.0001, figure 2). These results indicate that infliximab is effective for treating uveitis attacks and reducing the occurrence of extraocular manifestations in patients with BU.

Figure 1

Frequency of uveitis attacks during 6 months before (pre), 6 months after (post6M) and 12 months after (post12M) infliximab treatment. Uveitis attacks during the 6-month period before the treatment were 3.7±2.2. During the 6- and 12-month periods after the treatment, the number of attacks was 0.6±0.7 and 0.3±0.9, respectively. The frequency of uveitis attacks before treatment was significantly different from the attacks at 6 and 12 months (p<0.0001, both).

Figure 2

Behçet disease current activity form (BDCAF) score during 6 months before (pre), 6 months after (post6M) and 12 months after (post12M) infliximab treatment. The BDCAF score during the 6-month period before treatment was 1.63±0.54. During the 6- and 12-month periods after the treatment, the BDCAF scores were 0.20±0.41 and 0.15±0.49, respectively. The BDCAF score before treatment was significantly different from the scores at 6 and 12 months (p<0.0001, both).

The mean EQ-5D scores before starting infliximab differed significantly from those at 6 and 12 months after treatment (p<0.0001, figure 3). The pretreatment and post-treatment mean subscale scores and composite score from the NEI VFQ-25 are shown in table 2. The composite score (p=0.0001), general health score (p=0.0001) and mental health score (p=0.0001) at 6 and 12 months after infliximab administration were significantly higher than the scores before treatment. The scores for general and mental health were 31.3 and 43.4 at 6 months before treatment and 73.8 and 91.9 at 6 months and 77.5 and 92.6 at 12 months after treatment, indicating a considerable improvement with infliximab. These results show that infliximab therapy is effective for improving QoL and quality of vision in patients with BU.

Table 2

The National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25) composite and subscale score in patients with Behçet disease before and after receiving infliximab (IFX) treatment

Figure 3

The EuroQol-5D questionnaire (EQ-5D) score during 6 months before (pre), 6 months after (post6M) and 12 months after (post12M) infliximab treatment. The EQ-5D score during the 6-month period before the treatment was 0.66±0.17. At 6 and 12 months after treatment, the EQ-5D scores were 0.97±0.08 and 0.96±0.07, respectively. The EQ-5D score before treatment was significantly different from the scores at 6 and 12 months (p<0.0001, both).

Discussion

Previous studies have indicated that severe BU has a detrimental effect on HR-QoL, with low health utility scores. Responses in the pretreatment stage in this study confirm a diminished HR-QoL among patients with moderate-to-severe BU. This diminished HR-QoL is characterised by anxiety, frustration, depression and a feeling of being generally unwell.

In this study, patients treated with infliximab had a greater improvement in overall EQ-5D scores at 6 and 12 months, in comparison with pretreatment scores and had large improvements in all dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. We also found that infliximab therapy improved the composite NEI VFQ-25 scores, with the responses showing that the majority of patients had improvements in general health, mental health and general vision, compared with the pretreatment stage. Patients also showed significantly improved social functioning. These results indicate that infliximab treatment substantially improved HR-QoL and VR-QoL. In a previous report evaluating the QoL of patients with BU using the NEI VFQ-25, interferon α-2a improved patients’ QoL significantly.2 Because we used a different treatment, we cannot make direct comparisons; however, our study suggests similar results.

This study also showed that infliximab significantly reduces the frequency of uveitis attacks and overall disease activity in patients with BU. These results are similar to those found in previous studies of the efficacy of infliximab for BU. The frequency of uveitis attacks was significantly reduced from 1 to 6 months and from 7 to 12 months after initiation of infliximab, compared with before treatment. Improvement of ocular and extraocular manifestations by infliximab might have contributed to the improved EQ-5D and VFQ-25 responses. Therefore, improvement of extraocular manifestations by infliximab may be a clinically meaningful benefit in comparison with conventional agents, although the impact of conventional agents on extraocular manifestations in BU has not been directly investigated.

Infliximab has been used in Japan for treatment of refractory BU from 2007, after approval by the Japanese Ministry of Health, Labour and Welfare. Previously, ciclosporin was used as an immunosuppressive treatment; however, central nervous system involvement occurs more often in patients with BU treated with ciclosporin than in those treated with other drugs.18 With infliximab, central nervous system involvement has not been reported to date. Thus, the efficacy and safety of infliximab may be better than with conventional treatment and may confer considerable additional value for the patient with moderate-to-severe BU.

Based on these results, infliximab infusion every 8 weeks at 5 mg/kg body weight may be sufficient to control BU in most patients. However, we advocate shortening the infusion interval when patients develop resistance to treatment, as has been reported for the treatment of various types of uveitis.19

The study has two limitations. First, is the absence of a control group. We believe that a control group with BU, treated with conventional immunosuppressive agents, would be ideal. Without the controls, we cannot conclude that the improvement in QoL is only attributable to infliximab. Second, our study had a relatively short follow-up period of 12 months. The efficacy and safety of infliximab may decrease gradually, and long-term efficacy and safety cannot be extrapolated from the short-term results. Therefore, studies with longer-term follow-up are required. Within these limitations, we conclude that infliximab therapy improves health- and vision-related QoL, and reduces uveitis attacks and extraocular manifestations. These results should facilitate the ease of obtaining informed consent for treatment of BU with biological agents, by informing patients of the specific efficacy of infliximab therapy and its favourable effects on QoL and vision.

References

Footnotes

  • Contributors Each author certifies that they have made substantial contribution to the work reported in this manuscript by participating in at least one of the following three areas: (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content and (3) final approval of the version to be published.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Provided by the local ethics committee of Jikei University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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